PEPH Ophthalmology Department8 th March 2012

OCULAR MANIFESTATIONS OF SYPHILIS

“HE WHO KNOWS SYPHILIS, KNOWS MEDICINE”

SIR WILLIAM OSLER

Acquired syphilis divided into primary, secondary, tertiary stages by Philippe Ricord (1800-1889). Ricord’s chancre is the parchment-like initial lesion of syphilis.

Treponema Pallidum, first isolated by Schaudin in 1904 and reported in 1905.

STAGING AND DISCOVERY

Despite a decade of steady decline, syphilis has re-emerged in the United States with outbreaks throughout the country in the past few years.

Ophthalmologists have the opportunity to play a key role in the early diagnosis and management of this potentially fatal disease.

SYPHILIS: RE-EMERGENCE OF AN OLD ADVERSARY.

THE NATIONAL ANTENATAL SENTINEL HIV AND SYPHILIS PREVALENCE SURVEY, SOUTH AFRICA,

2010, NATIONAL DEPARTMENT OF HEALTH

SYPHILIS BY PROVINCE

Before clinical signs or symptoms appear, and within a few hours after inoculation, T.pallidum travels via the lymphatic system to regional lymph nodes and then throughout the body via the blood stream.

Invasion of the central nervous system can occur during any stage of syphilis.

 Organism cannot be grown in vitro – there are still many questions.

PATHOGENESIS

Kanski:The absence of pathognomonic signs and the ability of syphilis to mimic any ocular and systemic inflammatory disease often leads to misdiagnosis and delay in appropriate treatment.

THE GREAT MASQUERADE

1. Primary syphilis Eye chancre (Conj

chancre) 2. Secondary

Orbit and eyelids Eyelid rash Orbital periostitis Dacryocystitis Dacryoadenitis Madarosis

Anterior segment Conjunctivitis Interstitial keratitis Episcleritis, scleritis Uveitis

Posterior segment Chorioretinitis Neuroretinitis Retinal vasculitis

Neuroophthalmic Optic neuritis CN palsies

3. Tertiary Anterior segment

findings similar to secondary syphilis (intersitial keratitis, uveitis etc.)

Lens subluxation Neuroophthalmic

Pupils Argyll Robertson pupil Tonic pupils Homer's syndrome RAPD (optic atrophy)

Others CN palsies Ptosis Nystagmus VF defects

Gumma of ocular structures

TIEN WONG – OCULAR SYPHILIS

Eye chancre (Conj chancre) Orbit and eyelids

Eyelid rash Orbital periostitis Dacryocystitis Dacryoadenitis Madarosis

PRIMARY

INTERSTITIAL KERATITIS

SCLERITIS, EPISCLERITIS

UVEITIS: IRIS PAPULES, NODULES,

ROSEOLAE

POSTERIOR SEGMENTCHORIORETINITIS, NEURORETINITIS,

RETINAL VASCULITIS

OPTIC NEURITIS

CRANIAL NERVE PALSIES

Pupils Argyll Robertson Adies Horner's syndrome RAPD (optic atrophy)

PapilloedemaRetrobulbar neuritisPerioptic neuritisPtosisNystagmusOcular Motility disordersVisual Field defectsGumma

NEURO-OPHTHALMIC

PUPILS

Douglas Moray Cooper Lamb Argyll RobertsonScottish ophthalmologist, born 1837; died 1909. In 1869 Argyll Robertson described the phenomenon in two articles. 

VDRL with t itre Detects antibodies

directed against host antigens such as cardiolipin which are released following tissue damage by T.pallidum

Low sensitivity False positive in EBV,

mycoplasma, autoimmune disease, chronic liver disease and malignancy

False negative in HIV RPR FTA-ABS TPHA Darkfield Microscopy Silver staining

aspirated fluids

TESTS

VDRL with titre False positive in

EBV, mycoplasma, autoimmune disease, chronic liver disease and malignancy

False negative in HIV RPR FTA-ABS TPHA Darkfield

Microscopy Silver staining

aspirated fluids PCR

TESTS

VDRL:First developed in 1906 by Harris, Rosenberg and Reidel

at the Veneral Disease Research Laboratory

PROZONE:The prozone phenomenon in syphilis testing refers to a

false negative response resulting from overwhelming antibody titers which interfere with the proper formation of the antigen-antibody lattice network necessary to visualize a positive flocculation test. This prozone effect in syphilis testing can be expected in cases of disproportionately high antibody titers, such as secondary syphilis, or with human immunodeficiency virus (HIV) coinfection.

VDRL AND THE PROZONE PHENOMENON

FTA-Abs negative – no treatmentFTA-Abs positive and VDRL negative

If previous treatmentFTA Abs positive and VDRL positive

4 fold reduction in titre post treatment Should reduce to 1:4 or less within 1 year in primary

syphilis, 2 years in secondary syphilis and 5 years in syphilis

A VDRL of <1:8 eg 1:4 does not decrease Therefore treat if not previously treated or no decrease in titre

on previous treatment

INDICATIONS FOR TREATMENT

Screen partners and children

Neurosyphil is : Peneci l l in G: 12-24 MU IV dai ly x 10-15 days Procaine Peneci l l in 2.4 MU IM dai ly and oral Probenecid 2g dai ly x 10-15 days

Syphil is with ocular signs, but normal CSF: Procaine Peneci l l in 2.4 MU IM dai ly x 3 weeks

Penecil l in allergic Ceftr iaxone 2g IV/ IM x 10-14 days Tetracyc l ine/Erythromycin 500mg qid x 30 days

+/- Steroids and cyc loplegics for anterior segmane inflammation

Historical note: Ju l ius Wagner Jauregg treated the previous ly incurable condit ion of General

Paralys is of the Insane with malaria and won the Nobel Pr ize in 1927. The ra ised temperature k i l led the spi rochaetes.

Peneci l l in or ‘mould ju ice’ was first discovered in 1928 by Alexander F leming

WILL’S TREATMENT

WORTH THE MONEY?

Discovered in 1928Mass Produced in 1944Fleming, Chain and Florey awarded

Nobel Prize in 1945.Post 1945 was the era of antibiotics

PENECILLIN ‘THE WONDER DRUG’

Jarisch-Herxheimer (dermatologists) Rapid onset within 2 hourse Fever, chills, myalgia, tacchycardia, hyperventilation,

vasodilation and hypotensionDue to release of endogenous pyrogen from the

spirochaetes50% with treatment of primary syphilis90% with treatment of secondary syphilisTreat:

Prednisone 60mg daily

REACTION TO TREATMENT

Is ocular syphilis neuro syphilisSyphilis and HIVLP or not LPDiagnostic Dilemma

CONTROVERSIES

?

Oxford Handbook of HIV Medicine 2009

“Ocular syphilis is best conceptualised as neurosyphilis and may develop in people who have been adequately treated for primary or secondary syphilis. All patients should be referred to ophthalmologist for 10 days of IV penecillin”

CLASSIFICATION

The possible potentiating effects of HIV on Treponema pallidum infection suggest the need for lumbar puncture in the evaluation of HIV-seropositive patients with syphilis.

PCR testing is a useful adjunct in the diagnosis of infectious causes of posterior uveitis. Cases with vascular or optic nerve inflammation, extensive retinitis, or immunocompromise are more likely to have positive PCR results and may benefit from PCR testing of aqueous humor.

SYPHILIS AND HIV

Currently, the Center for Disease Control and Prevention and the European guidelines recommend a lumbar puncture (LP) among all HIV-infected patients with a late-latent syphilis or a syphilis of unknown duration.

Some other experts advise a LP for all patients coinfected by HIV and syphilis.

Because of the lack of clear indication of LP in HIV-infected patients with syphilis, in practice, LPs are performed at the discretion of the treating physician in many centers.

QUESTIONS FOR WARD ROUNDS: Why do an LP when you are going to treat with penecillin

anyway? Why do you repeat an LP?

LP OR NOT LP

CSF VDRL is specific, but not sensitive: High % false negative

CSF FTA-Abs is very sensitive, but not very specific: High false positive

THEREFORE: If CSF FTA-Abs is negative then neurosyphilis is ruled out.

(A very sensitive test couldn’t detect it). If CSF VDRL is positive neurosyphilis is confirmed. (A very

specific test with low sensitivity has detected it). In most cases the FTA-Abs will also be positive.

If CSF FTA-Abs is positive but the VDRL is negative you could be dealing with with a false positive test.

THEREFORE:Look at other parameters…

STELLENBOSCH PROTOCOL

Raised WBC >5Raised CSF proteinRaised IgG index – always send a yellow tube with

blood as well.

OTHER CSF PARAMETERS

Diagnosis is centered around a high level of clinical suspicion and includes treponemal specific and non-treponemal serologic tests

 In patients with HIV infection, clinicians should be vigilant for ocular syphilis despite normal cerebrospinal fluid measures

Non-treponemal tests may be negative in HIV-infected patients with ocular syphilis. 

DIAGNOSTIC DILEMMA

Syph i l i s : Re - em ergence o f an o ld ad ve r sa ry. Chao J R ,  Kh u rana R N ,   Fawz i A A ,  Reddy HS ,  Rao NA. O ph tha l mo l ogy.  2006 No v ; 113 (11 ) :2 074 - 9 .

Syph i l i s an d H I V I n f ec t i o n : A n Up da te N i co la M . Ze to la1 and J eff rey D . K laus ne r1 ,2 , C l i n i ca l I n f ec t i o us D i seas es 200 7 ; 4 4 :12 22–8

A l te r a t i o n i n th e Nat u ra l H i s to ry o f Neu ros yph i l i s b y Co ncu rren t I n f ec t i o n w i t h th e Hu man I mm uno defic i en cy V i ru s , D o na ld R. J o hns , M .D . , Mau reen Tie rney , M .D . , and Do nna Fe l sens te in , M .D . , N E ng l J Med 198 7 ; 3 16 :1 569 - 157 2 J une 18 , 1987

T he au tho r s co nc lu de tha t when t he CSF -V D R L i s no n reac t i ve , CSF - FTA and % C SF B ce l l s m ay he lp exc l ude o r e s tab l i sh the d i agno s i s o f n eu ro syph i l i s , C .M .  Ma rra ,   L .C .   Tan ta l o ,  C . L .  Maxwe l l ,   K .  Do ug he r t y ,  B .  Wo o d , A m er i can J o u rna l o f O ph th a lm o l o gyVo lum e 138 , I s sue 4   , Page 7 02 , O c t o be r 20 04

Po lymer ase Cha in Reac t i o n A n a l ys i s o f Aqueo us and V i t reo us Spec imen s i n the D i agno s i s o f Po s te r i o r Segm en t I n f ec t i o us U ve i t i s , T ho mas W.  Ha rpe r , D ar lene  M i l l e r ,   J o yce C .   Sch iffm an ,   J ane t L .  Dav i s , Am er i can J ou rna l o f O ph tha l mo l og yVo lum e 147 , I s sue 1   , Pages 140 - 1 47 .e2 , J anua ry 200 9

HI V and Syph i l i s : When t o Per f o rm a Lum bar Punc tu re , L i bo i s , A gnÈ s MD* ; De Wi t , S t É phane MD , Ph D* ; Po l l , BÉ nÉ d i c te* ; Ga rc i a , Fe l i pe MD , PhD† ; F l o renc e , E r i c MD , Ph D‡ ; D e l R i o , A na MD† ; Sanchez , Paq u i ta MD§ ; Neg redo , E ugen ia MD ∥ ; Vandenb r uaene , Marc M D‡ ; G at e l l , J o s É M . MD , PhD† ; C lu meck , Na th an MD , PhD* , S exua l l y Tr ansm i t ted D i seases :Ma rch 200 7 - Vo l um e 34 - I s su e 3 - pp 141 -14 4

O cu la r m an i fe s t a t i o ns an d t rea tm en t o f s yp h i l i s . K i s s S ,  Dami co FM ,  Yo un g L H . Semi n Op h tha lm o l .  200 5 J u l - Sep ; 20 (3 ) :1 61 - 7 .

O cu la r s yp h i l i s am o ng H I V- in f ec ted in d iv idu a l s . L i J Z ,   Tucke r J D ,   Lo bo A M , Ma rr a , C M,  Dav i s BT , Papa l i od i s GN , Fe l sen t e i n D ,  D u r an d ML ,Yawetz S ,  Ro bb ins GK . C l i n I n f ec t D i s .   201 0 A ug 15 ; 51 (4 ) :46 8 - 71 .

O cu la r s yp h i l i s am o ng H I V- in f ec ted pa t ien ts : a sy s tem at i c ana ly s i s o f the l i t e ra tu re J os ep h D Tu cke r , 1   J o na th an Z L i , 2  G reg or y K Ro bb ins , 1   Ben jam in T D av i s , 1   A nn - Ma r i e Lo bo , 3   J an Ku nke l , 4  Geo rge N Papa l i o d i s , 3  Mar l en e L D u r and , 1   an d Do nn a Fe l sens te in 1 Sex Trans m I n fec t .   201 1 Feb r ua r y ;   87 (1 ) : 4 –8

T he Pro z on e Pheno m eno n w i th Syp h i l i s and H I V- 1 Co - i n fec t i o n , G rego r y S mi t h , MD , and Ro be r t P. Ho lm an , MD So u t he rn Med i ca l J o u rna l • Vo l um e 9 7 , Num ber 4 , A p r i l 2 004

REFERENCES

HIERONYMUS FRACASTORIUS (GIROLAMO FRACASTORO) SHOWS THE SHEPHERD SYPHILUS AND THE HUNTER

ILCEUS BEING WARNED AGAINST YIELDING TO TEMPTATION WITH THE DANGER OF INFECTION WITH

SYPHILIS.

Anterior segment Conjunctivitis Interstitial

keratitis

INTERSTITIAL KERATITIS

Neurosyph i l is has several forms. I f the sp i rochete invades the CNS, syphi l i t i c mening i t is resul ts . Syphi l i t i c meningi t is is an ear ly mani fes tat ion, usual ly occurr ing wi th in 6 months o f the pr imary in fec t ion. CSF shows h igh pro te in , low g lucose, h igh lymphocyte count , and pos i t ive syphi l is sero logy.

Meningovascular syphi l is occurs as a resul t o f damage to the b lood vessels o f the meninges, bra in , and spinal cord , lead ing to in farc t ions caus ing a wide spect rum of neuro logic impai rments .

Parenchymal neurosyph i l is inc ludes tabes dorsa l is and general pares is . Tabes dorsal i s deve lops as the poster ior co lumns and dorsal roots o f the spinal cord are damaged. Poster ior co lumn impai rment resu l ts in impai red v ibra t ion and propr iocept ive sensat ion, leading to a wide-based gai t .

Disrupt ion of the dorsa l roots leads to loss o f pain and temperature sensat ion and are f lex ia. Damage to the cor t ica l regions o f the bra in leads to general pares is , former ly ca l led “general pares is of the insane,” which mimics o ther forms of dement ia. Impai rment of memory and speech, persona l i ty changes, i r r i tab i l i t y, and psychot ic symptoms deve lop and may advance to progress ive dement ia.

The Argy l l -Rober tson pupi l , a pup i l that does not react to l ight but does const r i c t dur ing accommodat ion, may be seen in tabes dorsal is and general pares is . The prec ise locat ion o f the les ion caus ing th is phenomenon is unknown.

http:/ /emedic ine.medscape.com/art ic le/1169231-overview

NEUROSYPHILIS

The Venereal Disease Research Laboratory (VDRL) and other nontreponemal tests for syphil is measure the levels of antibody directed against a cardiol ipin—lecithin antigen. False posit ive reactions can occur in patients with immunoglobulin abnormalit ies. Patients infected with the human immunodeficiency virus (HIV) often have polyclonal gammopathy, and a majority have anticardiolipin antibodies.1 False positive nontreponemal tests in patients with HIV make it difficult to evaluate the response to therapy in patients who have syphil is,

Until there is a more accurate test for active syphil is, such as one that identifies T. pall idum  antigen, cl inical judgment must be paramount in the approach to syphil is in HIV-infected patients. There should probably be a lower threshold for treatment, given the increased severity of syphil is in this population. 5

Util ity of the VDRL Test in HIV-Seroposit ive Patients, Joseph J. Drabick, M.D.Edmund C. Tramont, M.D., N Engl J Med 1990; 322:271January 25, 1990

TEST THE TEST